Chlorophenotffiazinecarboxamides



2,776,971 CHLOROPHENOTHIAZINECARBOXAMIDES ohn W. Cusic, Skkie, andMarkus Zimmermann, Evanston, Ill., asslgnors, by mesne assignments, toG. D. Searle & Co., Skokie, 111., a corporation of Delaware No Drawing.Application February 14, 1955,

' Serial No. 488,110

9 Claims. (Cl. 260- 243) This invention is concerned with a new group ofchlorophenothiazinecarboxamides and, more particularly, with thecompounds of the basic structunal formula and the non-toxic saltsthereof, wherein X is a halogen atom and preferably chlorine orfluorine, Alk 1s a lower alkylene radical separating the two nitrogenatoms attached thereto by at least two carbon atoms and NRR" is a memberof the class consisting of dialkylamlno and nitrogen containingheterocyclic radicals which are attached to the group Alk through anitrogen in the heterocycle.

In the foregoing structural formula the radical Alk represents abivalent, saturated, aliphatic hydrocarbon radical derived from astraight or branched-chain hydrocarbon :and which includes radicals suchasethylene,

propylene, butylene, amylene, hexylene and polymethylene radicals suchas trimethylene, tetramethylene, pentamethylene,rand hexamethylene. Theradicals R and R can represent such lower alkyl radicals as methyl,ethyl, straight and branched propyl, butyl, amyl, and hexyl radicals.The radical NRR" can also represent a nitrogen-containing radical suchas a piperazino, N-(lower alkyl)piperazino, thiamorpholino,tetrahydroquinolino, and tetrahydroisoquinolino radical, but of specialvalue for the purposes of this invention are heterocyclic radicals inwhich NR'R" represents pyrrolidino, piperidino, and morpholino radicals.p

p The organic bases of the foregoing type form pharmaceuticallyacceptable non-toxic salts with a variety of inorganic and strongorganic acids including sulfuric, phosphoric, hydrochloric, hydrobromic,sulfamic, citric, ascorbic, and related acids. They also form quaternaryammonium salts with a variety of organic esters of sulfuric, hydrohalicand aromatic sulfonic acids. Among. such esters are methyl chloride andbromide, ethylchloride, propyl chloride, butyl chloride, isobutylchloride, benzyl chloride and bromide, phenethyl bromide, naphthylchloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate,ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin,allyl bromide, methallyl bromide, and crotyl bromide.

In U. S. Patent No. 2,627,517, issued February 3, 1953, one of us (JohnW. Cusic) described certain nonhalogenated basically substitutedphenothiazineoarbox- :amides. It has now been found that by substitutionof a halogen atom in the phenothiazine moiety of these amides there areobtained medicinally valuable products with a pharmacological spectrumof activities ditferent from that shown by the non-halogenatedphenothiazinecarboxamides. Specifically, the compounds of this inventionhave a strong anti-emetic effect, a tranquilizing effect in cases ofhyperirritability and of over-stimulation of the ethyl acetate usingcharcoal decolorization yields N-(y- 2,776,971 Patented Jan. 8 1 957 ice2 central nervous system. Their eifect is directed specifically to thecentral nervous system and they do not share the activity of thepreviously described non-halogenated phenothiazinecarboxamides on thesympathetic nervous system. As an example, they'fail to show the potentinhibiting efiect of the action of acetylcholine on the intestineexhibited by the compounds of U. S. Patent No. 2,627,517.

The invention will be described more fully in conjunction with thefollowing examples. However, it should be understood that these examplesare given by way of illustration only and that the invention is not tobe construed as limited in spirit or in scope by the details set forth.In these examples temperatures are given uncorrected in degreescentigrade and quantities of materials in parts by weight. i

Example 1 To a mixture of 60 parts of 2-chlorophenothiazine in 500 partsof toluene and 40 parts of vphosgene in parts of toluene, there areadded gradually 32 parts of pyridine. After stirring at room temperaturefor 90 minutes, the temperature is slowly raised to 80 C. When themixture has regained room temperature, 20 parts of phosgene in 50 partsof toluene are added and then, gradually, 16 parts of pyridine. Themixture is maintained at room temperature for 2 hours, after which it isgradually heated to C. and maintained at that temperature for 2 hours;

The mixture is then poured intoice water. The organic layer is washedrepeatedly with Water and then dried over' To this solution of2-chloro-l()-chloroformylphenothia- V zine there are added 37 parts ofN,N-dimethylethylenedi-- amine and the reaction mixture is refluxed for2 hours.

It is then cooled and extracted with dilute hydrochloricacid. Thisextract is rendered alkaline by addition of cold aqueous sodiumhydroxide solution and extracted withether. The ether extract is driedover anhydrous sodium. sulfate, filtered and evaporated. Onrepeatedrecrystal-- lization from ethanol and benzene and then fromethanol and ether, the N-(fl-dimethylaminoethyl)-2-chloro-l0--phenothiazinecarboxamide is obtained in very fine color--- less needles.

Treatment of an ether solution of this base with 1 molecular equivalentof hydrogen chloride in propanol' causes precipitation of ahydrochloride which, recrys tallized from a mixture of ethyl acetate andethanol using charcoal clarification melts at about ZOO-201 C. This.

salt has the structural formula N o l o 0-Nn on2 21y(om)1 irol Example 2To a solution of 56 parts of Z-chloro-lO-chloroformylphenothiazine in990 parts of toluene are added 41 parts ofN,N-dimethyltrimethylenediamine and the mixture is refluxed for 2 hours.it is then cooled and extracted with dilute hydrochloric acid. Theextract is rendered alkaline with dilute sodium hydroxide solution andthe dimethylamiuopropyl) 2 chloro l phenothiazinecarboxamidehydrochloride melting at 176477" C.

Example 3 A mixture of 56 parts of2-chloro-l0-chloroforrnylphenothiazine and 46 parts ofN,N-diethylethylenediamine in 800 parts of butanone is refluxed for 2hours, concentrated to one-fifth of its original volume, diluted withether and extracted with dilute hydrochloric acid. This acid extract isrendered alkaline by addition of dilute sodium hydroxide solution andextracted with ether. The ether solution is dried over anhydrous sodiumsulfate, filtered and evaporated. The residue is dissolved in dryethanol and one equivalent of hydrogen chloride in propanol is added. Onconcentration of the resulting mixture the hydrochloride separates as anoil. Repeated crystallization from acetone and a small amount of ethanolyields the hydrochloride of N-diethylarninoethyl-2-chloro-l0phenothiazinecarboxamide melting at about ZOO-201 C.

Example 4 To a. solution of 11.9 parts ofZ-chloro-l0-chloroformylphenothiazine in 120 parts of butanone are added10.4 parts of N,N-diethyltrimethylenediarnine and the mixture is heatedat reflux for 2 hours. 'It is then poured into ice water and the aqueoussolution is washed with ether, rendered alkaline by addition of sodiumhydroxide and extracted with ether. The ether extract is dried overanhydrous sodium sulfate, filtered and evaporated. The residue,containing the N(- diethylaminopropyl)-2-chloro-lO-phenothiazinecarboxamide, is taken up in ether and treatedwith one equivalent of hydrogen chloride in propauol. Recrystallizedrepeatedly from a mixture of alcohol and acetone using charcoalclarification, the hydrochloride melts at about 184-185" C.

Example 5 in Z-propauol yields a crystalline hydrochloride which,

recrystallized from butanone, melts at about l88-l90 C. The compound hasthe structural formula Example 6 A solution of 127 parts of3-chloro-10-chloroformylphenothiazine and 110 parts ofN-(fl-aminopropyD-pyrrolidine in 2000 parts of butanone is refluxed for3 hours, concentrated to about 400 parts, diluted with ether and treatedwith aqueous hydrochloric acid. The aqueous layer is separated, washedwith ether, rendered alkaline by the addition of dilute "sodiumhydroxide solution and then extracted with ether. This extractis driedover anhydrous calcium sulfate, filtered and evaporated to yield A theyellowish oily N-(fl-pyrrolidinopropyl)-3chloro-l0-phenothiazinecarboxarnide. It has the structural formula N CHz-OH:

(llO-NEP-C H-O HI'N (3H3 CH2CH:

Example 7 A solution of 78 parts of2-chloro-10-chloroformylphenothiazine and 33.4 parts ofN-(fi-aminoethyumorpholine in 400 parts of butanone is refluxed for anhour and then poured into ice water. The aqueous solution is washed withether, rendered alkaline with sodium carbonate, and then extracted withether. This extract is dried over anhydrous potassium carbonate,filtered, treated with one equivalent of gaseous hydrogen chloride in2-propanol, and evaporated. The residue is dissolved in ethanol,clarified with charcoal and then treated with ethyl acetate andconcentrated to yield the hydrochloride of N (p morpholinoethyl) 2chloro 10 phenothiazinecarboxamide melting at about 192193 C. Thecompound has the structural formula O 0NH-(CHz): 0

i OKs-C inn Example 8 13 parts of N-phenyl-4-fluoroanthranilic acid areheated to about 270 C. for minutes and then dissolved in ether. Theether solution is washed with 2-N sodium hydroxide and with water andthen dried over anhydrous sodium sulfate. After evaporation of the etherthe residue is distilled at about 0.05 mm. pressure and 70 C. to yieldm-fluorodiphenylamine as a colorless oil. A mixture of 3.7 parts of thisoil, 1.3 parts of sulfur and 0.1 part of iodine are heated at 180195 C.for an hour. The residue is sublimed in vacuum and then crystallizedrepeatedly from ethanol to yield Z-fiuorophenothiazine melting at aboutZOO-201 C.

Reaction of this compound with phosgene in toluene by the method ofExample 1 yields a toluene solution of2-fiuoro-10-chloroformylphenothiazine. A solution of 5 3 parts of thiscompound and 69 parts of N-(6-aminobutyl)- diisopropylamine in 1000parts of toluene is refluxed for 2 hours. It is then cooled and treatedwith dilute hydrochloric acid. The aqueous layer is separated, renderedalkaline with dilute sodium hydroxide and extracted with ether. Thisether extract is dried over anhydrous sodium sulfate, filtered andevaporated to yield as a residue N (5 diisopropylaminobutyl) 2 fluoro 10phenothiazinecarboxamide in the form of a yellow resin.

Example 9 By the procedure of the foregoing example3-fluorophenothiazine is prepared which melts at about 176177 C.Substitution of 58 parts of this compound for the 2-chlorophenothiazineused in Example 1 yields the N (5 dimethylaminoethyl) 3 fluoro 10phenothiazinecarboxamide in the form of a light orange resin.

What is claimed is:

1. A compound of the structural formula 6 wherein X is a halogen atom ofan atomic weight less wherein Alk is a lower alkylene radical separatingthe than 40, Alk is a lower alkylene radical separating the two nitrogenatoms attached thereto by at least two two nitrogen atoms attachedthereto by at least two carbon atoms and n is a positive integer lessthan 3. carbon atoms and NR'R" is a member of the class con- 7. Acompound of the structural formula sisting of di-(lower)alkylamino,pyrrolidino, piperidino 5 and morpholino radicals.

2. A compound of the structural formula S\ v N CH2C z 01 lTT wherein Alkis a lower alkylene radical separating the two nitrogen atoms attachedthereto by at least two carbon atoms.

3. A compound of the structural formula I| T CHZ-CHZ *01 o ONHAlk-'N 8.A compound of the structural formula 4. A compound of the structuralformula wherein Alk is a lower alkylene radical separatlng the twonitrogen atoms attached thereto by at least two carbon atoms. \N 01 9. Acompound of the structural formula CONH(CHz)2N(CH3)z 5. A compound ofthe structural formula CHa-C n OO-NH-(GH2)e-N(QH3)2 6. A compound of thestructural formula References Cited in the file of this patent UNITEDSTATES PATENTS 2,627,517 Cusic Feb. 3, 1953 \N OH2 CHI 2,645,640Charpentier July 1953 J0NH N FOREIGN PATENTS 1,060,715 France APL 5, 9

1. A COMPOUND OF THE STRUCTURAL FORMULA